Pediatric acute lymphoblastic leukemia—Conquering the CNS across the choroid plexus

März, Martin; Meyer, Svenja; Erb, Ulrike; Georgikou, Christina; Horstmann, Martin; Hetjens, Svetlana; Weiß, Christel; Fallier‐Becker, Petra; Vandenhaute, Elodie; Ishikawa, Hiroshi; Schroten, Horst; Dürken, Matthias; Karremann, Michael

doi:10.1016/j.leukres.2018.07.001

Cited by 18 publications

(17 citation statements)

References 40 publications

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“…Therefore, transmigration of lymphoblasts facilitated by exosome-associated conditioning of the barriers might well be due to more sophisticated mechanisms than just disruption of tight junctions and barrier breakdown, but e.g., by the induction of receptor expression or cytokine signaling [3,4,18]. In this regard, we could previously show transcellular migration of lymphoblasts across the choroid plexus epithelium, hence, disruption of tight junction proteins may not be necessary at all to cross the blood-CNS barriers and degradation of tight junction proteins may not be the only exosome-mediated pathway to facilitate lymphoblast invasion to the brain [21].…”

Section: Exosome Conditioning Does Not Alter Bcsfb Integritymentioning

confidence: 92%

“…Therefore, we investigated the relevance of leukemia-derived exosomes on ALL cell transmigration across the blood-cerebrospinal fluid barrier (BCSFB). Recently, we could establish a human in vitro model suitable to study the cellular interactions of leukemic blasts with the choroid plexus epithelial cells and demonstrate crossing of lymphoblasts by a transcellular and paracellular route [21]. Now, we provide evidence that leukemia-derived exosomes may facilitate this process of transmigration into the CNS compartment without destruction of the BCSFB integrity.…”

Section: Introductionmentioning

confidence: 87%

“…HiBCPP cells were used as an in vitro model of the BCSFB as previously described [ 21 ]. In brief, 7.5–9 × 10 4 HiBCPP cells were seeded on the bottom side of an inverted 24-well-filter insert with a pore size of 5 μm (Sarstedt, Nümbrecht, Germany) in DMEM/F12 (Ham) supplemented with 5 μg/mL insulin and 10% FCS (Thermo Fisher, Dreieich, Germany) and adhered for 24 h under standard conditions (37 °C, 5% CO 2 , 95% humidity.)…”

Section: Methodsmentioning

confidence: 99%

“…When the predilection of CNS involvement in T-ALL hijacks these pathways [18], the BCSFB within the choroid plexus might well represent a significant gate into the CNS. Several studies have addressed this potential entry site [7,20,21], but so far, have described only limited lymphoblast transmigration across the BCSFB [3,49]. However, pediatric ALL presents with only subtle symptoms in most patients, and time to diagnosis is often prolonged.…”

Section: Translational Implicationsmentioning

confidence: 99%

“…4 × 10 5 labeled ALL cells were placed in the upper compartment of BCSFB in vitro model for 6 h at 37 • C in DMEM/F12 (Ham) supplemented with 0.5% BSA. CXCL12 (100 ng/mL, Peprotech, Cranbury, NJ, USA) was used in the lower compartment as chemoattractant as previously established [21]. The barrier integrity was measured at the beginning and end of each experiment by TEER.…”

Section: Transmigration Assaymentioning

confidence: 99%

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The Impact of Small Extracellular Vesicles on Lymphoblast Trafficking across the Blood-Cerebrospinal Fluid Barrier In Vitro

Erb

Hikel

Meyer

et al. 2020

IJMS

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Central nervous System (CNS) disease in pediatric acute lymphoblastic leukemia (ALL) is a major concern, but still, cellular mechanisms of CNS infiltration are elusive. The choroid plexus (CP) is a potential entry site, and, to some extent, invasion resembles CNS homing of lymphocytes during healthy state. Given exosomes may precondition target tissue, the present work aims to investigate if leukemia-derived exosomes contribute to a permissive phenotype of the blood-cerebrospinal fluid barrier (BCSFB). Leukemia-derived exosomes were isolated by ultracentrifugation from the cell lines SD-1, Nalm-6, and P12-Ichikawa (P12). Adhesion and uptake to CP epithelial cells and the significance on subsequent ALL transmigration across the barrier was studied in a human BCSFB in vitro model based on the HiBCPP cell line. The various cell lines markedly differed regarding exosome uptake to HiBCPP and biological significance. SD-1-derived exosomes associated to target cells unspecifically without detectable cellular effects. Whereas Nalm-6 and P12-derived exosomes incorporated by dynamin-dependent endocytosis, uptake in the latter could be diminished by integrin blocking. In addition, only P12-derived exosomes led to facilitated transmigration of the parental leukemia cells. In conclusion, we provide evidence that, to a varying extent, leukemia-derived exosomes may facilitate CNS invasion of ALL across the BCSFB without destruction of the barrier integrity.

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Section: Exosome Conditioning Does Not Alter Bcsfb Integritymentioning

confidence: 92%

Section: Introductionmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Translational Implicationsmentioning

confidence: 99%

Section: Transmigration Assaymentioning

confidence: 99%

See 3 more Smart Citations

The Impact of Small Extracellular Vesicles on Lymphoblast Trafficking across the Blood-Cerebrospinal Fluid Barrier In Vitro

Erb

Hikel

Meyer

et al. 2020

IJMS

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The choroid plexus stroma constitutes a sanctuary for paediatric B‐cell precursor acute lymphoblastic leukaemia in the central nervous system

Fernández-Sevilla

Valencia

Flores‐Villalobos

et al. 2020

The Journal of Pathology

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Despite current central nervous system‐directed therapies for childhood B‐cell precursor acute lymphoblastic leukaemia, relapse at this anatomical site still remains a challenging issue. Few reports have addressed the study of the specific cellular microenvironments which can promote the survival, quiescence, and therefore chemoresistance of B‐cell precursor acute lymphoblastic leukaemia cells in the central nervous system. Herein, we showed by immunofluorescence and electron microscopy that in xenotransplanted mice, leukaemic cells infiltrate the connective tissue stroma of the choroid plexus, the brain structure responsible for the production of cerebrospinal fluid. The ultrastructural study also showed that leukaemia cells are able to migrate through blood vessels located in the choroid plexus stroma. In short‐term co‐cultures, leukaemic cells established strong interactions with human choroid plexus fibroblasts, mediated by an increased expression of ITGA4 (VLA‐4)/ITGAL (LFA‐1) and their ligands VCAM1/ICAM1. Upon contact with leukaemia cells, human choroid plexus fibroblasts acquired a cancer‐associated fibroblast phenotype, with an increased expression of α‐SMA and vimentin as well as pro‐inflammatory factors. Human choroid plexus fibroblasts also have the capacity to reduce the proliferative index of leukaemic blasts and promote their survival and chemoresistance to methotrexate and cytarabine. The inhibition of VLA‐4/VCAM‐1 interactions using anti‐VLA‐4 antibodies, and the blockade of Notch signalling pathway by using a γ‐secretase inhibitor partially restored chemotherapy sensitivity of leukaemia cells. We propose that the choroid plexus stroma constitutes a sanctuary for B‐cell precursor acute lymphoblastic leukaemia cells in the central nervous system. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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Glymphatic system dysfunction in pediatric acute lymphoblastic leukemia without clinically diagnosed central nervous system infiltration: a novel DTI-ALPS method

Lin

Hou

et al. 2023

Eur Radiol

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Pediatric acute lymphoblastic leukemia—Conquering the CNS across the choroid plexus

Cited by 18 publications

References 40 publications

The Impact of Small Extracellular Vesicles on Lymphoblast Trafficking across the Blood-Cerebrospinal Fluid Barrier In Vitro

The Impact of Small Extracellular Vesicles on Lymphoblast Trafficking across the Blood-Cerebrospinal Fluid Barrier In Vitro

The choroid plexus stroma constitutes a sanctuary for paediatric B‐cell precursor acute lymphoblastic leukaemia in the central nervous system

Glymphatic system dysfunction in pediatric acute lymphoblastic leukemia without clinically diagnosed central nervous system infiltration: a novel DTI-ALPS method

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